Loss of NAT10 Reduces the Translation of Kmt5a mRNA Through ac4C Modification in Cardiomyocytes and Induces Heart Failure

作者：Ting Xu, Tailai Du, Xiaodong Zhuang, Xin He, Youchen Yan, Jialing Wu, Huimin Zhou, Yan Li, Xinxue Liao, Jiangui He, Chen Liu, Yugang Dong, Jing‐Song Ou, Shuibin Lin, Demeng Chen, Zhan‐Peng Huang · 发表于：Journal of the American Heart Association · 年份：2024 · DOI：10.1161/jaha.124.035714 · 被引用次数：14 · 研究领域：RNA modifications and cancer、RNA and protein synthesis mechanisms、HVDC Systems and Fault Protection

Background In the past decade, the biological functions of various RNA modifications in mammals have been uncovered. N4‐acetylcytidine (ac4C), a highly conserved RNA modification, has been implicated in human diseases. Despite this, the involvement of RNA ac4C modification in cardiac physiology and pathology remains incompletely understood. NAT10 (N‐acetyltransferase 10) stands as the sole acetyltransferase known to catalyze RNA ac4C modification. This study aims to explore the role of NAT10 and ac4C modification in cardiac physiology and pathology. Methods and Results Cardiac‐specific knockout of NAT10, leading to reduced RNA ac4C modification, during both neonatal and adult stages resulted in severe heart failure. NAT10 deficiency induced cardiomyocyte apoptosis, a crucial step in heart failure pathogenesis, supported by in vitro data. Activation of the p53 signaling pathway was closely associated with enhanced apoptosis in NAT10‐deficient cardiomyocytes. As ac4C modification on mRNA influences translational efficiency, we employed ribosome footprints coupled with RNA sequencing to explore genome‐wide translational efficiency changes caused by NAT10 deficiency. We identified and validated that the translational efficiency of Kmt5a was suppressed in NAT10 knockout hearts due to reduced ac4C modification on its mRNA. This finding was consistent with the observation that Kmt5a protein levels were reduced in heart failure despite unchanged mRNA expression. Knockdown of Kmt5a in...